Oral sustained release pharmaceutical formulation and process

ABSTRACT

A pharmaceutical sustained release tablet or tablet layer is formed by making a wet granulation, using povidone (PVP) in water or alcohol-water as the granulating fluid which is mixed with a pharmaceutical active, hydroxyethyl cellulose, a wicking agent e.g. microcrystalline cellulose, then drying and milling the granulation and blending with dry powdered erosion promotor, e.g. pregelantinized starch, additional wicking agent, lubricant e.g. magnesium stearate and glidant e.g. silicon dioxide, and compressing the resultant granulation, which upon administration results in a slow release of the pharmaceutical active.

This is a continuation-in-part of U.S. Ser. No. 299,178 filed Jan. 19,1989 which in turn is a continuation-in-part of U.S. Ser. No. 78,138filed July 27, 1987 which issued Apr. 11, 1989 as U.S. Pat. No.4,820,522. This invention relates to a sustained release pharmaceuticaldosage, and is more particularly concerned with a pharmaceutical activecontaining matrix formed from granulations of active mixed with inactivepowdered excipients plus hydroxyethyl cellulose (HEC) using an aqueoussolution of Povidone U.S.P. (polyvinylpyrrolidone-PVP) as thegranulating agent, which granulations are dried, milled, blended withadditional inactive powdered excipients, and then compressed into atablet, and to the process of making the pharmaceutical-containingmatrix in a manner so that the rate of release of the pharmaceutical canbe varied or controlled.

BACKGROUND OF PRESENT INVENTION

It is desirable to extend the dosing interval of many pharmaceuticalswhile maintaining the initial plasma concentrations achievable withconventional tablets or caplets. This would provide immediate andextended therapeutic effect and reduce the number of doses necessary,thereby making therapy more convenient. A way to do this has now beenfound, using the present invention, whereby two tablets or caplets canbe formulated to provide both immediate release and sustained release orsustained release alone such that the dosing interval can be extended toat least eight (8) hours.

The matrix of the present invention can be used to make sustainedrelease pharmaceutical preparations in compressed tablet form. Thematrix materials used are compressed into a shaped tablet form. The term"tablet" as used herein includes tablets of any shape, and includescaplets, which are tablets having a capsule shape. The tablets may becoated with a pharmaceutically acceptable coating material or havepharmaceutically acceptable coloring added to the composition prior tocompression.

SUMMARY OF THE INVENTION

The present invention, in its process aspect is directed to the processof preparing pharmaceutical sustained release shaped and compressedtablet characterized by a slow release of the pharmaceutical active uponadministration comprising the following steps:

(A) forming a granulating agent by dissolving 5-25 parts by weightpovidone in water or in an alcohol-water mixture;

(B) blending together in parts by weight of the total composition thefollowing ingredients with sufficient pharmaceutical active to compriseabout 68 to 94 percent by weight of the total composition in dry powderform 5-25 parts by weight hydroxyethyl cellulose and 5-25 parts byweight of a wicking agent e.g. microcrystalline cellulose;

(C) adding and mixing the granulating agent from Step A to the blendedpowders from Step B, to form a wet granulation;

(D) drying the wet granulation of Step C;

(E) milling the dried granulation from Step D;

(F) thoroughly blending the milled dried granulation from Step E withthe following parts by weight of the total composition of ingredients indry powder form: 1-15 parts by weight erosion promoter, e.g.pregeletanized starch, 5-45 parts by weight wicking agent, e.g.microcrystalline cellulose, 0-10 parts by weight lubricant, e.g.magnesium stearate, and 0-5 parts by weight glidant, e.g. silicondioxide; and

(G) compressing the final granulation from Step F into a tablet ortablet layer.

The mixing of the granulating agent and blended powders in Step C ispreferably accomplished in a high shear granulator (mixer).

In its product aspect the present invention is directed to a shaped andcompressed sustained release therapeutic composition comprising apharmaceutical active, granulating agent and excipients combined into amatrix, characterized by a slow release of the active medicament uponadministration, wherein the granulating agent and excipients includes acombination of two polymers, hydroxyethyl cellulose and povidone, and awicking agent and erosion polymer and wherein the total amount of thenon-active ingredients in the sustained release matrix is from about 6to about 32 percent by weight of the total composition. In morepreferred embodiments, the amount of non-active ingredients is less thanabout fifteen (15) percent of the weight of said shaped and compressedcomposition.

The preferred tablets of this invention include a shaped and compressedpharmaceutical sustained release tablet made by wet granulating fromabout 68 to about 94 percent by weight of the total composition ofactive and the excipients ingredients of Part I with the granulatingagent of Part II, drying and milling the resultant granulations, andthen blending with the excipients of Part III and compressing into atablet, wherein the ingredients of parts I, II and III comprise thefollowing:

    ______________________________________                                        Ingredient         Parts by Weight                                            ______________________________________                                        Part I                                                                        excipients                                                                    hydroxyethyl cellulose                                                                           5-25                                                       microcrystalline cellulose                                                                       5-25                                                       Part II                                                                       granulating agent                                                             povidone           5-25                                                       water or alcohol-water                                                                           q.s                                                        Part III                                                                      excipients                                                                    pregelatinized starch                                                                            2-15                                                       microcrystalline cellulose                                                                       5-45                                                       magnesium stearate 0-10                                                       colloidal silicon dioxide                                                                        0-5                                                        ______________________________________                                    

The invention preferably is utilized in the form of a bi-layer tabletcontaining both an immediate release layer and a sustained releaselayer.

In preferred embodiments of the invention the pharmaceutical active iswater soluble and is selected from the group consisting of codeine;codeine phosphate; loperamide; aspirin; naproxen; propoxyphene HCl;meperidine HCl; dipenhydramine; pseudoephedrine; and anypharmaceutically acceptable salts thereof.

In addition to the hydroxyethyl cellulose and PVP polymers discussedabove which are "matrix binding agents", the preferred excipients whichare granulated with the active include a "wicking agent" (to wick fluidsinto the matrix) preferably, microcrystalline cellulose. Additionalexcipients which are preferably added to the granulated and driedingredients include an additional amount of a wicking agent, preferablymicrocrystalline cellulose, an erosion promoter, preferablypregelatinized starch, and preferably a lubricant such as magnesiumstearate and optionally a glidant such as colloidal silicon dioxide.

DETAILED DESCRIPTION OF THE INVENTION

The sustained release matrix pharmaceutical tablets of the presentinvention are made by adding granulating agent to a dry powder blend ofactive drug and inactive excipients to form wet granulations, which arethen dried and finely divided, e.g. by milling the dried granulationsinto a finer powder form, then blending with additional inactivepowdered excipients and compressing into tablets. Tablets can be readilymanufactured using conventional tableting equipment.

The tablets of the present invention have novel and advantageousfeatures. A primary advantage is that the tablets are bioerodible whenswallowed, that is, no insoluble tablet shaped device remains to beexcreted or removed from the body after the active medicament isdepleted from the tablet. The sustained release matrix uses hydroxyethylcellulose (hydroxyethyl cellulose NF) and povidone (povidone USP)(Plasdone® K29/32) (PVP) as the Matrix Binding Agents for obtaining thesustained release effect. This combination of two well-knownpharmaceutically acceptable polymers with an erosion promoter andwicking agent, in the relative proportions and in the manner used hereis believed to be a major novel feature of the present invention. In themost preferred embodiments of the invention, the amount of hydroxyethylcellulose used is on the general order of four percent or less of theamount of active medicament, while the amount of povidone is on thegeneral order of four percent or less of the amount of active medicamentused. This means the sustained release matrix of the present inventionis capable of producing dosage forms having very high drug/matrixbinding agent ratios. This results in reducing the size or number oftablets needed, making the product easier to swallow, less expensive andmore desirable to the consumer.

Another advantage of this invention is that the rate of matrix erosionwhen the tablet is swallowed can be modified so that the degree and/orlength of the sustained release effect of the matrix can be easilymodified by simply altering the levels of the other excipients, asidefrom the hydroxyethyl cellulose and the povidone (PVP). Hence, the rateat which the pharmaceutical active is released from the tablet andsubsequent absorption from the gut into the bloodstream can be modifiedto match the desired blood plasma concentration versus time profile.

The sustained release matrix of the present invention can be used aloneas a shaped and compressed tablet (tablet can be any shape such as oval,round, caplet or spherical), or as part of a multi-layered tabletcontaining an immediate or quick-release layer to elevate the bloodlevels of active medicament quickly and also containing a sustainedrelease portion to maintain the elevated blood level. Hence, the presentinvention can be used to prepare tablets with two or more layers, eachwith a significantly different release rate of the same component, or toprepare tablets of different components where a combination of drugs isdesired.

The sustained release matrix, in our currently preferred embodiments,contains approximately to the nearest one percent three percenthydroxyethyl cellulose, three percent povidone (PVP), five percent of awicking agent such as microcrystalline cellulose and three percent of anerosion promoter such as pregelatinized starch with the balanceconsisting of active and various pharmaceutically acceptable, commonexcipients. The matrix tablets or tablet layers of the present inventionhave a very high active drug-to-excipients ratio on the order of 85percent active to 15 percent excipients by weight. This results in adrug-to-total matrix weight ratio of approximately 1:1.2.

As discussed, the hydroxyethyl cellulose and PVP polymers are matrixbinding agents. The additional excipients that are granulated with theactive include a wicking agent (to wick fluids into the matrix) such asmicrocrystalline cellulose. Additional excipients that are added to thegranulated and dried ingredients include additional wicking agent suchas microcrystalline cellulose, an erosion promoter such aspregelatinized starch, and preferably a lubricant such as magnesiumstearate.

For each of the particular ingredients used in the sustained releasematrix of the present invention, aside from the active, the hydroxyethylcellulose, and the povidone (PVP) there exists less preferredalternative or equivalent materials which could be used instead. Thefollowing Table I lists each of the various preferred ingredients, thepurpose of the ingredient, the preferred weight of such preferredingredient, the usable weight range of the preferred ingredient, otherless preferred alternatives or equivalents which can be substituted forthe preferred ingredient, the preferred weight of such alternateingredient and the usable weight range of such alternate ingredientneeded for a sustained release layer containing 325 mg of active. Formatrices (tablets or caplets) of a higher or lower level of active, theamounts of ingredients and their ranges would be proportionatelyincreased or decreased.

The ingredients are listed in Table I under Part I Active andExcipients, Part II Granulating Agent, Part III Excipients, since theyare used in this manner in the process by which the tablets of thepresent invention are made.

The preferred process which is utilized to form the most preferredsustained release matrix of the present invention is to mix together thedry powdered active drug, the dry powdered matrix binding agent,hydroxyethyl cellulose, and the dry powdered wicking agent,microcrystalline cellulose in a mixer/granulator. A granulating fluid orsolution is formed by dissolving povidone into water at a ratio of 19.1grams of povidone to 100 grams of water. The resultant granulating agentis sprayed onto the above admixed powders while they are being mixed inthe mixer/granulator so as to form a wet granulation. The wetgranulation thus obtained is dried and milled. At this point, a smallamount of dry powdered excipients such as pregelatinized starch,microcrystalline cellulose and magnesium stearate are added, and mixedwith the milled granulations, after which they are compressed therebyforming the sustained release matrix.

The preferred levels of active used in the sustained-release matrix ofthe invention utilizing the ingredients listed in Table 1 are from about68 to 94% active medicament ingredient and conversely from about 6 to32% inactive ingredients by weight of the total composition of thesustained release matrix. This percentage of active versus non-active(granulating agent and excipients) ingredients is consistent with theweight of ingredients given in Table 1. For example, utilizing 325 mg ofactive and the minimal ranges of non-active ingredients described inTable 1 a total matrix weight of 347 mg is achieved which would be325/347 or about 94% active, conversely 6% non-active by weight of thetotal composition. Utilizing 325 mg of active and the maximal ranges ofnon-active ingredients described in Table 1 a total matrix weight of 475is achieved which would be 325/475 or about 58% active, conversely 32%non-active by weight of the total composition.

                                      TABLE I                                     __________________________________________________________________________    SUSTAINED RELEASE ACETAMINOPHEN MATRIX                                                            (mg)               (mg)                                                       Wt. per                                                                            (mg)          Wt. per                                                                            (mg)                              Preferred Ingredient                                                                        Purpose                                                                             Tablet                                                                             Range                                                                             Alt. or Equiv.                                                                          Tablet                                                                             Range                             __________________________________________________________________________    Part I - Active & Excipients                                                  Pharmaceutical Active                                                                       Active                                                                              325  --  --        --   --                                Hydroxyethyl Cellulose                                                                      Matrix                                                                              10.7 5-25                                                                              --        --   --                                NF (Natrosol*/250L)                                                                         Binding                                                                       Agent                                                           Microcrystalline Cellulose                                                                  Wicking                                                                             Powdered Cellulose                                        NF, (Avicel*  Agent 10.7 5-25                                                                              (Solka Floc*)                                                                           10.7 5-25                              OG k9km k92m k93m k95)                                                        Part II - Granulating Agent                                                   Povidone, USP Matrix                                                                              10.7 5-25                                                                              --        --   --                                (Plasdone* K29/32)                                                                          Binding                                                                       Agent                                                           Purified Water,                                                                             Solvent                                                                             q.s  water-alcohol (up to 50%)                            USP                                                                           Part III - Excipients                                                         Microcrystalline Cellulose                                                                  Wicking    Powdered Cellulose                                   USP (Avicel*  Agent 15.0 5-45                                                                              (Solka Floc*)                                                                           15.0 5-45                              PH 101, 103, 103, 103)                                                        Pregelatinized                                                                              Erosion                                                                             5.0  2- 15                                                                             Starch NF 5.0  5-10                              Starch, NF    Promoter       (corn,                                           (corn, wheat, or             wheat or                                         potato source)               potato)                                                                       or                                                                            rice starch,                                                                  Sodium    3.0  1-10                                                           Starch                                                                        Glycolate                                                                     NF (Explotab*)                                                                Croscarmellose                                                                          3.0  1-10                                                           Sodium                                                                        NF (Ac Di Sol*)                                                               Crospovidone                                                                            3.0  1-10                                                           NF(PoVIDone*XL)                                  Silicon Dioxide                                                                             Glidant                                                                             0.0  0-5                                                  Magnesium     Lubricant                                                                           5.0  0-10                                                                              Stearic   5.0  5-10                              Stearate NF                  Acid NF                                          __________________________________________________________________________

EXAMPLE I Acetaminophen Sustained Release Bi-Layer Tablet

This example illustrates a bi-layer tablet in which there is both animmediate release layer and a sustained release layer. The immediaterelease layer is analogous in composition and manufacturing procedure tocurrently available over-the-counter acetaminophen non-sustained releasetablets. It is the sustained release layer that utilizes the matrix ofthe present invention. The acetaminophen content of the entire tablet is650 mg.

The bi-layer tablet uses the following ingredients:

    ______________________________________                                        Ingredient              mg/Tablet                                             ______________________________________                                        A. Immediate Release Layer                                                    Part I - Active and Excipients                                                acetaminophen, USP      325.0   mg                                            powdered cellulose, NF  42.3    mg                                            pre-gelatinized starch, NF                                                                            16.0    mg                                            Part II - Granulating Agent                                                   starch, NF              26.0    mg                                            purified water USP      q.s.                                                  Part III - Excipients                                                         Sodium laurel sulphate, NF                                                                            0.75    mg                                            magnesium stearate, NF  2.0     mg                                            Total                   412.05  mg                                            B. Sustained Release Layer                                                    Part I - Active and Excipients                                                Acetaminophen, USP      325.0   mg                                            hydroxyethyl cellulose, NF                                                                            10.7    mg                                            (NATROSOL* 250L)                                                              microcrystalline cellulose, NF                                                                        10.7    mg                                            (AVICEL* PH 101)                                                              Part II - Granulating Agent                                                   povidone, USP           10.7    mg                                            (PLASDONE* K29/32)                                                            Purified water, USP     q.s                                                   Part III - Excipients                                                         microcrystalline cellulose, USP                                                                       15.0    mg                                            (AVICEL* PH 101)                                                              pregelatinized starch, NF                                                                             5.0     mg                                            *STARCG 1500)*                                                                magnesium Stearate, NF  5.0     mg                                            Total                   382.1   mg                                            Total Tablet Weight     794.15  mg                                            ______________________________________                                    

The above ingredients are utilized to make a bi-layer tablet, by thefollowing working directions:

Working Directions

A. Immediate Release Layer

1. Weigh the components of Part I and add them to the bowl of a fluidbed granulator (AEROMATIC).

2. Prepare the granulating agent (Part II) by adding the purified waterto a processing tank (approximately 15 grams water for each gram ofstarch NF). Slowly mix in the starch and heat the mixture until thetemperature reaches 82° C.-84° C.

3. With the components of Part I in a heated fluidized state (inlet airtemperature 75° C. to 85° C.), spray the granulating agent onto thepowders.

4. After all the granulating agent has been sprayed, dry the granulatedpowders to a moisture content of 1.4-1.9% as determined by loss ondrying (e.g. Computrac).

5. Sieve the dried granulation (e.g. Glatt Quick Sieve: Stator No. 3,Screen No. 1.5mm, 1000 RPM). Other machines such as FitzpatrickCommunition Mill can be used.

6. Blend the sieved and dried granulation with the powders of Part IIIusing a suitable mixer such as a twin-shell, ribbon or planetary mixer.

B. Sustained Release Layer

1. Weigh the components of Part I and preblend in a high shear mixer(Fielder: impeller speed of approximately 250 RPM for 1 minute).

2. Prepare the granulating agent (Part II) by dissolving the povidoneUSP in the purified water USP (a ratio of 19.1 grams of povidone to 100gm of water).

3. Spray the granulating agent at a rate of 400 ml/min onto Part I inthe high shear mixer. Granulate the mixture for one minute after theaddition of Part II (Fielder: impeller speed of approximately 3000 RPM).

4. Remove the completed wet granulation from the high shear mixer andload it into the product bowl of a fluid bed apparatus (e.g. Aeromaticor Glatt). With an inlet air temperature of approximately 60° C., drythe granulation to a moisture level of 2.0 to 2.5% as determined by losson drying (e.g. Computrac). The wet granulation can also be dried ontrays in drying ovens.

5. Sieve the dried granulation (Glatt Quick Sieve: 1.5 mm Screen,Stator, No. 3, 305 RPM). Other machines such as a FitzpatrickCommunition Mill can be used.

6. Blend the sieved and dried granulation with the powders of part IIIusing a suitable mixer such as a twin-shell, ribbon or planetary mixer.

C. Compression of Tablets or Caplets

1. Load the granulation of the immediate release layer into one hopperand the granulation of the sustained release layer into the secondhopper of a bi-layer tableting machine (e.g. Stokes Versapress).Compress tablets using 0.749×0.281×0.060 extra deep concave capsuleshaped tooling (Tablet Tooling of other shapes such as oval or round canalso be used). The sustained release layer has a target weight of 382.1mg and the immediate release layer has a target weight of 412.05 mg.Ideal tablet hardness immediately after compression is J-12 Kp.

The bi-layer tablets of Example I were tested in twelve adult male humansubjects and compared to non-sustained release (immediate release only)tablets in a cross-over design. Two tablets of Example I, whichcontained 1300 mg of acetaminophen, were dosed at time=0 hour. Thenon-sustained release tablets, each containing 500 mg acetaminophen weredosed as two tablets (1000 mg acetaminophen) also at time=0 hour.Subjects were fasted at least 8 hours prior to administration of thedose. Blood samples were taken from each subject at 0, 1, 1.5, 2, 3, 4,6, 8, 10 and 12 hours. Plasma was separated from the blood and theconcentration of acetaminophen in each sample was determined. Theresults are shown numerically in Tables 2a and 2b. The results show thattwo bi-layer tablets of Example I, when compared to two tablets ofnon-sustained release acetaminophen (1000 mg dose), achieve thefollowing: comparable rate of absorption; comparable maximum plasmaconcentration; and comparable extent of absorption (AUC or area underthe curve) when adjusted for dose. Theoretically, the 1300 mg doseshould provide 130% of the AUC of the 1000 mg dose. The results fromTables 2 a and 2b show comparable extents of absorption by the followingcalculation: (64.3 mcg/ml divided by 49.5 mcg/ml)×100%=130%.

The tablets of Example I provide the opportunity to dose 30% moreacetaminophen in a more convenient manner by extending the dosinginterval to at least eight hours.

                  TABLE 2a                                                        ______________________________________                                        Sustained Release Acetaminophen 650 mg bi-layer tablets.                      (Example I) Average Plasma Concentration Levels of                            Acetaminophen (mcg/ml) in twelve subjects after                               administration of two tablets (1300 mg). Average AUC                          equaled 64.3 mcg/hr.                                                          TIME (HOURS) POST DOSING                                                      0    1.0    1.5    2.0   3.0  4.0  6.0 8.0  10.0 12.0                         ______________________________________                                        Average (mcg/ml)                                                              0    12.5   12.8   11.9  10.0 7.5  4.4 2.6  1.6  1.0                          ______________________________________                                    

                  TABLE 2b                                                        ______________________________________                                        Non-sustained Release Acetaminophen 500 mg tablets.                           Average Plasma Concentration Levels of Acetaminophen                          (mcg/ml) in twelve subject. Average AUC equaled 49.5                          mcg/hr.                                                                       TIME (HOURS) POST DOSING                                                      0    1.0    1.5     2.0  3.0  4.0 6.0  8.0 10.0  12.0                         ______________________________________                                        Average (mcg/ml)                                                              0    12.1   11.4    10.0 7.3  5.3 2.9  1.8 1.1   0.6                          ______________________________________                                    

EXAMPLE II Acetaminophen Sustained Release Tablet Containing 650 mg ofAcetaminophen in Matrix Form

This example illustrates an all-matrix (mono-layer) tablet in whichthere is only a sustained release layer. The working directions areanalogous to the working directions for the sustained release layerdescribed in Example I except that the amounts of all ingredients areproportionally increased such that the final tablet contains 650 mgacetaminophen. Tablets can be compressed using capsule, oval, round orother appropriately shaped tooling. The final target weight of thecompressed tablet is 764.2 mg.

    ______________________________________                                        Ingredient              mg/Tablet                                             ______________________________________                                        Part I - Active and Excipients                                                acetaminophen, USP      650.0   mg                                            hydroxyethyl cellulose, NF                                                                            21.4    mg                                            (NATROSOL* 250L)                                                              microcrystalline cellulose, NF                                                                        21.4    mg                                            (AVICEL* PH 101)                                                              Part II - Granulating Agent                                                   povidone, USP           21.4    mg                                            (PLASDONE* K29/32)                                                            purified water, USP     q.s                                                   Part III - Excipients                                                         microcrystalline cellulose, NF                                                                        30.0    mg                                            (AVICEL* PH 101)                                                              pregelatinized starch, NF                                                                             10.0    mg                                            (STARCH 1500*)                                                                magnesium stearate, NF  10.0    mg                                            Total                   764.2   mg                                            ______________________________________                                    

EXAMPLE III Acetaminophen/Pseudoephedrine Sustained Release Bi-layerTablet

This example illustrates a bi-layer tablet which is analagous to thetablet described in Example I, except pseudoephedrine is added to theacetaminophen as a second active ingredient and all amounts of activeand non-active ingredients per tablet and final weight of the tablet areproportionally increased.

    ______________________________________                                        Ingredient              mg/Tablet                                             ______________________________________                                        A. Immediate Release Layer                                                    Part I - Active and Excipients                                                acetaminophen, USP      333.33  mg                                            pseudoephedrine hydrochloride, USP                                                                    30.00   mg                                            powdered cellulose, NF  43.4    mg                                            pregelatinized starch, NF                                                                             16.4    mg                                            Part II - Granulating Agent                                                   starch, NF              26.7    mg                                            purified water, USP     q.s                                                   Part III - Excipients                                                         sodium laurel sulfate, NF                                                                             0.77    mg                                            magnesium stearate, NF  2.05    mg                                            Total                   452.65                                                B. Sustained Release Layer                                                    Part I - Active and Excipients                                                acetaminophen, USP      333.33  mg                                            pseudoephedrine hydrochloride, USP                                                                    30.0    mg                                            hydroxyethyl cellulose, NF                                                                            11.0    mg                                            (NATROSOL* 250L)                                                              microcrystalline cellulose, NF                                                                        11.0    mg                                            (AVICEL* PH 101)                                                              Part II - Granulating Agent                                                   povidone, USP           11.0    mg                                            (PLASDONE* K29/32)                                                            purified water, USP     q.s                                                   Part III - Excipients                                                         microcrystalline cellulose, NF                                                                        15.4    mg                                            (AVICEL* PH 101)                                                              pregelatinized starch, NF                                                                             5.13    mg                                            (STARCH 1500*)                                                                magnesium stearate, NF  5.13    mg                                            Total                   421.94  mg                                            Total Tablet Weight     874.64  mg                                            ______________________________________                                    

EXAMPLE IV Aspirin Sustained Release Bi-layer Tablet

This example illustrates a bi-layer tablet which is analogous to thetablet described in Example I, except a lesser amount of aspirin issubstituted for acetaminophen and all amounts of ingredients per tabletand final weight of the tablet are proportionally decreased. Onepractical amount of aspirin would be 250 mg such that the total amountof aspirin in a tablet would be 500 mg. The working directions for theimmediate release layer and the sustained release layer are analogous tothe working directions described in Example I. Tablets can be compressedusing capsule, oval, round or other appropriately shaped tooling. For atablet containing a total of 500 mg aspirin, the sustained release layerhas a target weight of 293.89 mg and the immediate release layer has atarget weight of 316.92 mg.

    ______________________________________                                        Ingredient              mg/Tablet                                             ______________________________________                                        A. Immediate Release Layer                                                    Part I - Active and Excipients                                                aspirin, USP            250     mg                                            powdered cellulose, NF  32.5    mg                                            pregelatinized starch, NF                                                                             12.3    mg                                            Part II - Granulating Agent                                                   starch, NF              20.0    mg                                            purified water, USP     q.s                                                   Part III - Excipients                                                         sodium laurel sulfate, NF                                                                             0.58    mg                                            magnesium stearate, NF  1.54    mg                                            Total                   316.92  mg                                            B. Sustained Release Layer                                                    Part I - Active and Excipients                                                aspirin, USP            250.0   mg                                            hydroxyethyl cellulose, NF                                                                            8.23    mg                                            (NATROSOL* 250L)                                                              microcrystalline cellulose, NF                                                                        8.23    mg                                            (AVICEL* PH 101)                                                              Part II - Granulating Agent                                                   povidone, USP           8.23    mg                                            (PLASDONE* K29/32)                                                            purified water, USP     q.s                                                   Part III - Excipients                                                         microcrystalline cellulose, NF                                                                        11.54   mg                                            (AVICEL* PH 101)                                                              pregelatinized starch, NF                                                                             3.85    mg                                            (STARCH 1500*)                                                                magnesium stearate, NF  3.85    mg                                            Total                   293.89  mg                                            Total Tablet Weight     610.81  mg                                            ______________________________________                                    

The scope of the present invention is not limited by the description,examples and suggested used herein and modifications can be made withoutdeparting from the spirit of the invention. For example, othercomponents may be added to the tablets including additional actives,various flavorings, preservatives and other pharmaceutical excipients.The present invention may also be used to provide sustained releaseforms for vitamins, minerals or other nutrients.

Application of the compositions and processes of the present inventionfor medical and pharmaceutical uses can be accomplished by any clinical,medical and pharmaceutical methods and techniques as are presently andprospectively known to those skilled in the art. Thus it is intendedthat the present invention cover the modifications and variations ofthis invention provided that they come within the scope of the appendedclaims and their equivalents.

We claim:
 1. A process of preparing a pharmaceutical-sustained releaseshaped and compressed tablet characterized by a slow release ofpharmaceutical active upon administration comprising the followingsteps:(A) forming a granulating agent by dissolving 5-25 parts by weightof the total composition of povidone in water or in an alcohol-watermixture; (B) blending together, in parts by weight of the totalcomposition, the following ingredients, with sufficient pharmaceuticalactive to comprise about 68 to 94 percent by weight of the totalcomposition, in dry powder form, 5-25 parts by weight hydroxyethylcellulose and 5-25 parts by weight of a wicking agent; (C) adding andmixing the granulating agent from Step A to the blended powders fromStep B, to form a wet granulation; (D) drying the wet granulation ofStep C; (E) milling the dried granulation from Step D; (F) thoroughlyblending the milled dried granulation from Step E with the followingparts by weight of the total composition of ingredients in dry powderform: 1-15 parts by weight erosion promoter, 5-45 parts by weightwicking agent, 0-10 parts by weight lubricant and 0-5 parts by weightglidant; and (G) compressing the final granulation from Step F into atablet or tablet layer.
 2. The process of claim 1 wherein:in Step B thewicking agent used is microcrystalline cellulose or powdered cellulose;and in Step F the erosion promoter used is 2-15 parts by weight ofeither pregelatinized starch or starch NF or rice starch, or is 1-10parts by weight of sodium starch glycolate or croscarmellose sodium orcrospovidone; the lubricant used is magnesium stearate or stearic acid;and the glidant used is colloidal silicon dioxide or fumed silicondioxide.
 3. The process of claim 2 wherein:in Step A, when any alcoholis used, it is alcohol USP or dehydrated alcohol USP or methyl alcoholUSP or isopropyl alcohol USP, and is used in a quantity equal to or lessthan the water in the alcohol-water mixture.
 4. The process of claim 2wherein:in Step A water is used; in Step B the wicking agent used ismicrocrystalline cellulose; in Step F the erosion promoter used ispregelatinized starch; and the lubricant used is magnesium stearate. 5.The process of claim 1 wherein the mixing of the granulating agent andblended powders in Step C is carried out in a high shear granulator. 6.A shaped and compressed sustained release therapeutic compositioncomprising a pharmaceutical active, a granulating agent and excipientscombined into a matrix, characterized by a slow release of thepharmaceutical active upon administration, wherein the granulating agentand excipients comprise hydroxyethyl cellulose, povidone, a wickingagent and an erosion promoter and wherein the total amount ofgranulating agent and excipients is effective to bind the active in asustained release solid matrix but is less than about 32 percent andmore than about 6 percent of the weight of said shaped and compressedcomposition.
 7. A composition according to claim 6 wherein the wickingagent is microcrystalline cellulose and the erosion promoter ispregelatinized starch.
 8. A composition according to claim 6 wherein byparts by weight of the total composition the granulating agent comprises5-25 parts by weight povidone and the excipients comprise 5-25 parts byweight hydroxyethyl cellulose, 10-70 parts by weight of a wicking agent,1-15 parts by weight of an erosion promoter, 0-10 parts by glidant.
 9. Acomposition according to claim 6 wherein by parts by weight of the totalcomposition the granulating agent comprises 5-25 parts by weight ofpovidone and the excipients comprise 5-25 parts by weight ofhydroxyethyl cellulose, 10-70 parts by weight of microcrystallinecellulose, 2-15 parts by weight pregelatinized starch 0-10 parts byweight magnesium stearate, and 0-5 parts by weight colloidal silicondioxide.
 10. A composition according to claim 6 wherein the total amountof granulating agent and excipients is greater than about 6 but lessthan 15 percent of the total weight of said shaped and compressedcomposition.
 11. A composition according to claim 9 wherein the totalamount of granulating agent and excipients is greater than about 6 butless than 15 percent of the total weight of said shaped and compressedcomposition.
 12. A composition according to claim 6 wherein thepharmaceutical active is selected from the group consisting of codeine;codeine phosphate; loperamide; aspirin; naproxen; propoxyphene HCl;meperidine HCl; diphenhydramine; pseudoephedrine; and anypharmaceutically acceptable salts thereof.
 13. A process of preparingsustained release bi-layer medicament tablet comprising a first layer ofimmediate release and a second layer of sustained slow release ofmedicament according to the steps of:(A) preparing an immediate releaselayer comprising a medicament and pharmaceutically acceptableexcipients; and (B) preparing a sustained release layer comprising amedicament as the active ingredient according to the steps of:(1)forming a granulating agent by dissolving about 5-25 parts by weight ofthe total sustained release layer of povidone in alcohol or analcohol-water mixture; (2) blending together a sufficient amount ofmedicament to comprise 68 to 94 percent of the total weight of thesustained release layer with the following ingredients in dry powderform in parts by weight of the total sustained release layer asindicated:

    ______________________________________                                        Ingredient       Parts by Weight                                              ______________________________________                                        hydroxyethyl cellulose                                                                         5-25                                                         wicking agent     5-25;                                                       ______________________________________                                    

(3) adding the granulating agent from Step 1 to the blended powders fromStep 2, and forming a wet granulation; (4) drying the wet granulation ofStep 3; (5) milling the dried granulation Step 4; (6) thoroughlyblending the milled dried granulation from Step 5 with the followingingredients in dry powder form;

    ______________________________________                                        Ingredient          Parts by Weight                                           ______________________________________                                        erosion promoter    1-15                                                      wicking agent       5-45                                                      lubricant           0-10                                                      glidant             0-5;    and                                               ______________________________________                                    

(C) combining and compressing the immediate release layer of Step A withthe sustained release layer of Step B into a bi-layered tablet.
 14. Ashaped and compressed bi-layer therapeutic composition comprising amedicament in a first immediate release layer and a medicament in asecond sustained release layer wherein the immediate release layercomprises a medicament and pharmaceutically acceptable excipients andthe sustained release layer comprises a medicament, a granulating agentand excipients combined into a matrix, wherein the granulating agent andexcipients of the sustained release layer include hydroxyethylcellulose, povidone, a wicking agent and erosion promoter and whereinthe total amount of said granulating agent and excipients is effectiveto bind the acetaminophen in a sustained release solid matrix but isless than about 32 percent of the weight of the sustained release layerof said shaped and compressed bi-layer composition.
 15. The therapeuticcomposition of claim 14 wherein the immediate release layer comprises amedicament which is the same as the medicament in the immediate releaselayer.
 16. The therapeutic composition of claim 14 wherein the amount ofgranulating agent and excipients is greater than about 6 percent butless than about 15 percent of the total weight of the sustained releaselayer of said shaped and compressed bi-layer composition.
 17. Thetherapeutic composition of claim 14 wherein the wicking agent ismicrocrystalline cellulose and the erosion promoter is pregelatinizedstarch.
 18. A shaped and compressed bi-layered immediate release layerand sustained release layer medicament tablet made by combining animmediate release layer comprising one or medicaments andpharmaceutically acceptable excipients with a sustained release layermade by wet granulating a sufficient amount of one or more medicamentsto comprise 68 to 94 percent of the total weight of the sustainedrelease layer with the Excipients of Part I and the Granulating Agent ofPart II, drying and milling the resultant granulations, and thenblending with the Excipients of Part III and compressing the two layersinto a tablet, wherein the ingredients of Parts I, II and III comprisethe following:

    ______________________________________                                                         Range of Parts by                                                             Weight of the Total                                          Ingredient       Sustained Release Layer                                      ______________________________________                                        Part I                                                                        Excipients                                                                    Hydroxyethyl Cellulose                                                                         5-25                                                         Microcrystalline Cellulose                                                                     5-25                                                         Part II                                                                       Granulating Aqent                                                             Povidone         5-25                                                         Alcohol or Alcohol-Water                                                                       q.s.                                                         Part III                                                                      Excipients                                                                    Pregelatinized Starch                                                                          2-15                                                         Microcrystalline Cellulose                                                                     5-45                                                         Magnesium Stearate                                                                             0-10                                                         Colloidal Silicon Dioxide                                                                      0-5                                                          ______________________________________                                    


19. A product made by the process of claim
 1. 20. A product made by theprocess of claim 14.